The present invention, in some embodiments thereof, relates to peptide agents for the treatment of oxidative stress related disorders.
Free radicals are extremely reactive chemical species that cause significant destruction in biological systems. Indiscriminate reaction of free radicals with biological molecules can lead to the destruction of cells and cellular components (e.g. mitochondria), thereby affecting physiological processes by causing cells to lose their structure and/or function.
In biological systems, free radicals are generally referred to as ‘reactive oxygen species’ (ROS). ROS are derived from endogenous sources via the metabolism of oxygen containing species, and from exogenous sources such as toxins and atmospheric pollutants.
Attack of ROS on biological molecules is referred to as ‘oxidative stress’. Oxidative stress has been implicated as a causative factor in a number of degenerative diseases.
Parkinson's disease (PD) is a multifactorial disease caused by both genetic and environmental factors. Although most patients suffering from PD have a sporadic disease, several genetic causes have been identified in recent years. An increasing number of genes that cause inherited forms of PD have provided the opportunity for new insights into the mechanisms at the basis of the disease. These genes include alpha-synuclein, parkin, PINK1, dardarin (LRRK2), and DJ-1.
Current concepts of the pathogenesis of PD center on the formation of ROS and the onset of oxidative stress leading to oxidative damage to substantia nigra pars compacta. Extensive postmortem studies have provided evidence to support the involvement of oxidative stress in the pathogenesis of PD; in particular, these include alterations in brain iron content, impaired mitochondrial function, alterations in the antioxidant protective systems (most notably superoxide dismutase [SOD] and reduced glutathione [GSH]), and evidence of oxidative damage to lipids, proteins, and DNA. Iron can induce oxidative stress, and intranigral injections have been shown to induce a model of progressive parkinsonism.
Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS), characterized by various symptoms of neurological dysfunction. MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are believed to result from autoimmune mediated activated immune cells such as T- and B-lymphocytes as well as macrophages and microglia. Pathologically, MS is characterized by perivenous infiltration of lymphocytes and macrophages into the CNS parenchyma, resulting in demyelinative lesions termed plaques. These plaques, which are the hallmark of MS, are associated with oligodendrocytes death, axonal damage and neuronal loss. The view that MS can be considered an inflammatory neurodegenerative disease is supported by studies demonstrating neuronal and axonal injury in regions remote from acute plaques, as well as imaging studies that demonstrated changes in normal appearing white and grey matter.
The etiology of MS has not yet been fully elucidated, and it has been attributed to both genetic and environmental causes. Accumulating data indicate that oxidative stress plays a major role in the pathogenesis of MS. Reactive oxygen species (ROS), leading to oxidative stress, generated in excess primarily by activated microglia, have been implicated as mediators of demyelination and axonal damage in both MS and EAE.
The neurotransmitter glutamate is one of the sources of oxidative stress in the MS primarily through activation of its ionotropic receptors. Oligodendrocytes, the myelin-producing cell of the CNS, are also highly vulnerable to glutamate excitotoxicity, mainly via the AMPA/kainate receptors. ROS causes damage to cardinal cellular components such as lipids, proteins and nucleic acids, resulting in cell death. Weakened cellular antioxidant defense systems in the CNS of MS patients resulting in increased vulnerability to ROS effects may increase CNS damage.
Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig's disease, is a progressive, fatal neurological disease affecting as many as 30,000 Americans with 5,000 new cases occurring in the United States each year. The disorder belongs to a class of disorders known as motor neuron diseases. ALS occurs when specific nerve cells in the brain and spinal cord that control voluntary movement gradually degenerate. Familial amyotrophic lateral sclerosis (FALS) is a form of ALS distinguished from the more common sporadic variant only by its familial background.
There is substantial evidence to support the hypothesis that oxidative stress is a contributor to motor neuron death. For example, it has been discovered that mutation of the anti-oxidant enzyme, superoxide dismutase 1 (SOD1), causes disease in a significant minority of cases.
DJ-1 is a small 189 amino acid protein that is ubiquitously expressed and highly conserved throughout diverse species. Accumulating data revealed its involvement in various cellular processes, especially in oxidative stress. DJ-1 is known to have several isoforms with isoelectric points between 5.5 and 7, with dominance of alkaline isoforms in normal conditions. Upon ROS exposure there is accumulation of more acidic isoforms of DJ-1, mediated through oxidation of cysteine residues [Bandopadhyay R, et al., Brain 127: 420-430, 2004; Canet-Aviles et al., Proc Natl Acad Sci USA 101: 9103-9108, 2004].
DJ-1 is widely distributed and is highly expressed in the brain, and is not confined to a single functional system or anatomical location. DJ-1 is expressed in neurons of different neurotransmitter phenotypes and in all glial cell types, such as astrocytes, microglia and oligodendrocytes. Recently DJ-1 mutations were discovered and associated with familial Parkinson's disease (PD) [Bonifati et al., 2003, Science 299: 256-9, 2003]. A post-mortem study of brain samples from sporadic PD brains versus control found that acidic isoforms of DJ-1 are more abundant in PD brains [Bandopadhyay R, et al., Brain 127: 420-430, 2004]. DJ-1 immunoreactivity was detected in other neurodegenerative diseases including multi-system atrophy, Alzheimer's disease, progressive supranuclear palsy, fronto-temporal dementia with parkinsonism linked to chromosome 17, and Pick's disease [Bandopadhyay R, et al., Brain 127: 420-430, 2004; Neumann N. et al., Acta Neuropathol (Berl) 107: 489-496, 2004; Rizzu P. et al., Ann Neurol 55: 113-118, 2004].
WO2007/119237 discusses an analysis of DJ-1 levels and activity for diagnosing oxidative stress related disorders.
U.S. Pat. Appl. No. 20060153807 and U.S. Pat. Appl. No. 20060171935 discusses vector mediated gene regulation of, e.g., DJ-1-associated agents for the treatment of neurodegenerative diseases such as Parkinson's.
WO2008/111063 discusses peptide agents capable of up-regulating DJ-1-dependent VMAT2 transcription for the treatment of neurodegenerative diseases.